The proposed project plans to develop a new strategy to prevent memory loss in Alzheimer's disease (AD) model mice. The strategy is based on a novel concept that selective local inhibition of the proteasome, a proteolytic complex that degrades protein substrates marked by attachment of ubiquitin molecules, is beneficial and can prevent the harmful effects of amyloid ? (A?) on long-term synaptic plasticity. The conventional wisdom is that in AD, pathological changes brought about by A? peptide accumulation or other causes of AD impair the ubiquitin- proteasome pathway and defective proteolysis exacerbates AD. Our unconventional approach stems from our observation that the proteasome performs different and often opposite functions in different parts of the neuron. Using hippocampal late phase long-term potentiation (L-LTP) as a model system for long-term synaptic plasticity, we found that inhibition of the nuclear proteasome impairs synaptic plasticity, while inhibition of th dendritic proteasome improves it. Therefore, we believe that although inhibition of the proteasome neuron-wide or in the nucleus would certainly exacerbate AD pathology, selective inhibition of the dendritic proteasome would help ameliorate synaptic deficits and memory impairment in AD. To test this idea, we devised a novel strategy to target a recombinant proteasome inhibitor specifically to dendritic spines in neurons. This recombinant inhibitor has a protein transduction domain (PTD) that enables it to traverse across the plasma membrane and enter neurons. Our preliminary data show that selective inhibition of the proteasome in dendritic spines can prevent the adverse A? effects on L-LTP and can restore normal L-LTP. Because the PTD technique has limitations for use in behavioral studies, now we plan to develop adeno-associated virus-mediated delivery into the hippocampus to test whether selective inhibition of the proteasome in dendritic spines can rescue memory deficits in AD model mice. This exploratory project will lay the groundwork for translating our research on the role of the proteasome in synaptic plasticity towards development of a new therapeutic strategy for ameliorating memory loss in AD.